Cardioprotection and safety of dexrazoxane (DRZ) in children treated for newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or advanced stage lymphoblastic leukemia (T-LL).

Abstract

9504 Background: POG 9404 evaluated the efficacy of DRZ as a cardioprotectant and its side effects in children receiving doxorubicin (DOX) as part of chemotherapy for T-ALL/T-LL. Methods: Between 6/1996 and 9/2001, 537 T-ALL/T-LL patients were treated with multi-agent chemotherapy that included 12 DOX doses of 30 mg/m2. Patients were randomized at diagnosis to treatment with or without DRZ (300 mg/m2 IV immediately prior to each DOX dose). Cardiac effects were assessed by serial echocardiograph measurements of left ventricular (LV) function (fractional shortening) and structure (end-diastolic dimension, wall thickness, and mass). Adverse events, grades 3-5 were recorded using CTCAE version 2.0. Results: Five-year EFS was similar for the DRZ (0.77±0.03%) and no-DRZ (0.76±0.03%) groups (p=0.9). Acute cardiac toxicity occurred in 1 patient (arrhythmia) on DRZ and 4 patients treated without DRZ (1-arrhythmia, 3-decreased LV fractional shortening). At each of the three time-points post-baseline (end-induction, after the last DOX dose and two years post study entry) LV dimensions were larger from baseline for patients who did not receive DRZ. In univariate analyses, change in LV end-diastolic dimension from baseline was the only variable that was significantly different between DRZ and no-DRZ arms. This was true at each of the three time points (p=0.005-0.02). The frequencies of grade 3 or 4 toxicity (hematologic, infection, CNS events, mucositis) or death were similar in groups with or without DRZ (p<0.24). There were 13 second malignancies, 10 patients had received DRZ and 3 had not (p=0.07). Conclusions: Our LV dimension measurements suggest that DRZ may protect against the early LV remodeling and enlargement that is seen with DOX cardiotoxicity. Addition of DRZ did not interfere with the anti-tumor efficacy of this DOX-containing, multi-agent regimen, and there was no significant increase in toxicities. An increased rate of second malignancies with DRZ did not reach conventional levels of statistical significance. The study was not powered to assess second malignancy rates and this trend is of unknown clinical significance.